Dysregulation of dopaminergic signaling is associated with several different neuropsychiatric diseases including Parkinson's disease (PD), depression, bipolar disorder, schizophrenia and addiction. The molecular mechanisms responsible for these alterations in dopamine signaling are largely unknown. There are two classes of dopamine receptor. D1-like receptors (D1R and D5R) are Gs-coupled excitatory GPCRs, while D2-like receptors (D2R, D3R and D4R) are Gi-coupled inhibitory GPCRs. Hence, these two receptor classes have opposing effects on neurotransmission, even though the endogenous ligand for all of these receptors is dopamine. Presumably, in a normal brain, there is an effective balance of D1-like and D2-like receptor responses. However, this balance becomes disrupted in the disease state for all the indications listed above. Indeed, D2Rs are significantly downregulated in untreated schizophrenic and bipolar patients (1-3), in patients with chronic depression and in patients with Parkinson's disease (PD) who have been treated with L-dopa and the other newer generation dopamine receptor agonist drugs. In recent work, my group has found that, following activation by dopamine agonist and endocytosis, distinct dopamine receptors are sorted differentially between recycling endosomes and lysosomes. Specifically, we found that the Gs-coupled D1R is recycled after undergoing endocytosis, while the Gi-coupled D2R is targeted for degradation in the lysosome after endocytosis. We also identified a protein, GPCR-associated sorting protein (GASP), which we believe is responsible for the targeting of several GPCRs, including the D2R, for degradation after endocytosis. Importantly, we found that some therapeutically important D2R agonists promote endocytosis and downregulation of D2Rs, while antagonist drugs at the D2R prevent dopamine-mediated endocytosis and downregulation of the D2R. Based on these studies, we hypothesize that agonist drugs that act at D2Rs (most of the PD drugs) would acutely enhance signaling through D2R (thereby substituting for the loss of dopamine neurons associated with this disease). However, during long-term use they would be expected to cause downregulation of D2R function. Selective degradation of D2Rs would, thereby, favor D1-Gs dopaminergic signaling after chronic use, which is thought to be responsible for dyskinesia associated with PD. In addition, we suggest that therapeutically relevant D2R antagonists may mediate their effects by facilitating upregulation/preventing downregulation of D2Rs. Importantly, while these antagonist drugs could restore the balance by upregulating D2Rs, their effectiveness would still be limited because D2Rs would not signal efficiently in the presence of the antagonist. Here, we will explore the effects of dopaminergic ligands on the trafficking of the dopamine receptors with the goal of identifying dopamine receptor agonists that can restore tone through these receptors without promoting their downregulation. PUBLIC HEALTH RELEVANCE: Dopaminergic drugs are used in the treatment of a number of psychiatric disorders. Classically, the efficacy and side effect profiles of these drugs have been attributed to varying pharmacokinetics, target selectively, and/or potency. Here we will examine the trafficking of the dopamine receptors in response to drug and determine whether biased agonism for signaling versus trafficking contributes to the pharmacological effects of these drugs.